During the past 20 years, there have been increasing concerns over the neurotoxicity of some organic solvents used in industry. For example, carbon disulfide (CD), 2,5-hexanedione (2,5-HD), and acrylamide have been linked to outbreaks of polyneuropathy in exposed workers. In each of these human disorders, exposure to the toxin results in degeneration of distal axons associated with accumulations of neurofilaments in distal portions of affected nerve fibers. However, the mechanism by which these axons produce their neurotoxicity in humans is unknown. In animal models of these disorders, neurobiological approaches can clarify the mechanisms and consequences of these toxic neuropathies. For example, our studies of acrylamide strongly suggest that the neurofibrillary axonal pathology results from a defect in slow axonal transport, particularly of neurofilament proteins. Our hypothesis is that similar alterations in transport of neurofilaments may result in the neurofibrillary pathology occurring in 2,5-HD and CD neuropathies. To study this issue, radiometric, gel fluorographic, and morphometric techniques will be used to assess the transport of specific polypeptides within the slow axonal transport system and to correlate these changes with the axonal pathology occurring following CD and 2,5-HD exposures. We suggest that high-dose, short-term administration of these two toxins will result in abnormalities similar to those occurring in acute acrylamide intoxication, while, at later stages, when distal axonal degeneration occurs, there will be a secondary response of neurons to axonal injury. Our studies are designed to differentiate the direct toxic affects of these agents from secondary consequences of axonal injury. Knowledge of mechanisms leading to toxic neurofibrillary axonal disorders has important implications for understanding the neurotoxicity of commonly used organic solvents known to produce human neurological disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004078-03
Application #
3251969
Study Section
Safety and Occupational Health Study Section (SOH)
Project Start
1985-12-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1989-11-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Type
Schools of Osteopathy
DUNS #
City
Stratford
State
NJ
Country
United States
Zip Code
08084